The present invention relates to a series of new amide and urea compounds having anti-hypercholesteremic activities and which can therefore be used in the treatment and prophylaxis of hypercholesteremia, arteriosclerosis and like disorders. The invention also provides methods and compositions using such compounds as well as processes for their preparation.
Among the causes of ischemic cardiac insufficiency (which may result in angina, myocardial infarction and the like) atherosclerosis is thought to be most important. It is believed that the foam cells under the endodermis cell layer of blood vessels accumulate cholesterol esters, and that this is a major cause of arteriosclerosis.
Inhibitors of acyl-CoA: cholesterol acyl transferase (hereinafter referred as ACAT) inhibit the synthesis of cholesterol esters in the foam cells, diminish the accumulation of cholesterol esters and inhibit the formation and development of atherosclerosis due to the accumulation of cholesterol esters.
Additionally, it has been established that there is a correlation between arterioselerosis and hypercholesterolemia. Cholesterols in food are absorbed as free cholesterol in the intestinal mucosal cell tract. They are then esterified by ACAT, and get into blood. Therefore, an ACAT inhibitor inhibits a rise in the cholesterol concentration in blood by inhibiting the absorption of food cholesterol into the blood.
For this reason, compounds having the ability to inhibit the activity of ACAT are useful for the treatment and prophylaxis of atheroscleosis.
The compounds of the present invention have a (9H-xanthen-9-yl)methyl group, a 6,11-dihydrodibenz-[b.e]oxepine-11-yl group, a (1-phenylcycloalkyl)methyl group, a p-alkoxyphenyl group or an alkyl group attached to an amido or ureido group. Compounds containing a (9H-xanthen-9-yl)methyl group are disclosed in Publications WO 93/06096 and EP 337375. Compounds containing a 6,11-dihydrodibenz[b.e]oxepine-11-yl group are disclosed in Publication EP 497201. Compounds containing a (1-phenylcycloalkyl)methyl group are disclosed in Publication EP 293880. Compounds containing a p-alkoxyphenyl group are disclosed in Publication EP 424194. Compounds containing an alkyl group are disclosed in Publication EP 283742. Diphenylurea compounds are disclosed in WO 92/03413. Other somewhat similar compounds are disclosed in EP Publications 439059 and 477778.
The compounds of the present invention, and especially those containing a (9H-xanthen-9-yl)methyl group, have surprisingly been found to have a much better inhibitory activity against ACAT than do the prior art compounds referred to above and/or have a much better oral absorbability.